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- Title
Insights into Network of Hot Spots of Aggregation in Nucleophosmin 1.
- Authors
Florio, Daniele; La Manna, Sara; Di Natale, Concetta; Leone, Marilisa; Mercurio, Flavia Anna; Napolitano, Fabiana; Malfitano, Anna Maria; Marasco, Daniela
- Abstract
In a protein, point mutations associated with diseases can alter the native structure and provide loss or alteration of functional levels, and an internal structural network defines the connectivity among domains, as well as aggregate/soluble states' equilibria. Nucleophosmin (NPM)1 is an abundant nucleolar protein, which becomes mutated in acute myeloid leukemia (AML) patients. NPM1-dependent leukemogenesis, which leads to its aggregation in the cytoplasm (NPMc+), is still obscure, but the investigations have outlined a direct link between AML mutations and amyloid aggregation. Protein aggregation can be due to the cooperation among several hot spots located within the aggregation-prone regions (APR), often predictable with bioinformatic tools. In the present study, we investigated potential APRs in the entire NPM1 not yet investigated. On the basis of bioinformatic predictions and experimental structures, we designed several protein fragments and analyzed them through typical aggrsegation experiments, such as Thioflavin T (ThT), fluorescence and scanning electron microscopy (SEM) experiments, carried out at different times; in addition, their biocompatibility in SHSY5 cells was also evaluated. The presented data clearly demonstrate the existence of hot spots of aggregation located in different regions, mostly in the N-terminal domain (NTD) of the entire NPM1 protein, and provide a more comprehensive view of the molecular details potentially at the basis of NPMc+-dependent AML.
- Subjects
NUCLEOPHOSMIN; NUCLEAR proteins; ACUTE myeloid leukemia; SCANNING electron microscopy; CYTOCOMPATIBILITY
- Publication
International Journal of Molecular Sciences, 2022, Vol 23, Issue 23, p14704
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms232314704